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Context: IL-6 (IL6) is an immune-modulating cytokine associated with obesity in humans. Objective: Our objective was to assess the associations between the genetic variability of IL6 gene and adiposity and long-term changes. Design and Subjects: We determined the linkage disequilibrium-tagging single-nucleotide polymorphisms of IL6 gene in 2255 healthy women and 980 healthy men from two prospective cohorts. We also conducted a metaanalysis on the associations between polymorphism −174G&amp;gt;C (rs1800795) and adiposity. Results: IL6 haplotype 222211 (possessing rs2069827, rs1800797, rs1800795, rs1554606, rs2069861, and rs1818879; 1 codes the common and 2 codes the minor alleles) was consistently and significantly associated with greater waist circumference (P = 0.009 in men; P = 0.0003 in women) and baseline body mass index (BMI) (P = 0.01 in men; P = 0.046 in women) compared with the most common haplotype 2. Haplotype 222211 was also associated with significantly higher early-adulthood BMI in women (P = 0.007). The haplotype-associated difference in BMI persisted significantly during the follow-up. A 5′ promoter polymorphism, rs2069827, was consistently associated with significantly higher early-adulthood BMI, baseline BMI, and waist circumference in men (carriers vs. noncarriers, P = 0.01, 0.007, and 0.008) and women (P = 0.01, 0.10, and 0.0016). The data from this study and a metaanalysis of 26,944 individuals did not support substantial relations between the best-studied polymorphism, −174G&amp;gt;C, and adiposity. Conclusions: Our data from two independent cohorts indicate that the variability of the IL6 gene is significantly associated with adiposity. Such associations are less likely to be caused by polymorphism −174G&amp;gt;C.

Interleukin-6 Genetic Variability and Adiposity: Associations in Two Prospective Cohorts and Systematic Review in 26,944 Individuals